Scientists build first synthetic yeast chromosome

An international team of scientists has built a modified yeast chromosome from scratch, the latest step in the quest to make the world's first synthetic yeast genome, an advance that would lead to new strains of the organism to help produce industrial chemicals, medicines and biofuels.

Instead of just copying nature, the team did extensive tinkering with their chromosome, deleting unwanted genes here and there. It then successfully incorporated the designer chromosome into living yeast cells, endowing them with new capabilities not found in naturally occurring yeast.

It is the most extensively altered chromosome ever built.- Jef Boeke, New York University

"It is the most extensively altered chromosome ever built," said Jef Boeke of New York University's Langone Medical Center, who led the effort. The findings were published on Thursday in an online edition of the journal Science.

While other teams have synthesized bacterium and viral DNA, Boeke's is the first report of a synthetic chromosome in a eukaryote, an organism whose cells contain a nucleus, like human cells.

Brewer's yeast

The achievement, which took seven years, involved the use of computer-aided design to construct one of 16 chromosomes in brewer's yeast, known scientifically as Saccharomyces cerevisiae.

The synthetic version, which the scientists call synIII, is a slimmed-down version of the yeast's naturally occurring chromosome III, which has 316,667 base pairs. The team picked this chromosome because it is the smallest and controls how yeast cells mate and undergo genetic change.

"We have shown that yeast cells carrying this synthetic chromosome are remarkably normal. They behave almost identically to wild yeast cells, only they now possess new capabilities and can do things that wild yeast cannot," said Boeke. Such methods could be used to improve yeast's ability to thrive in harsh environments, such as very high concentrations of alcohol.

Boeke, formerly of Johns Hopkins University, joined NYU in January to head the newly formed Institute for Systems Genetics.

Jim Collins of Boston University and a pioneer in the field called Boeke's work a "tour-de-force in synthetic biology," an emerging field of science which applies the principles of engineering to living systems.

"This development enables new experiments on genome evolution and highlights our ever-expanding ability to modify and engineer DNA," said Collins, whose lab won a Gates Foundation grant in 2012 to engineer a probiotic yogurt bacterium to neutralize cholera infections.

Synthetic biology is best known for work done by genome scientist and entrepreneur Craig Venter, who in 2010 reported he had built the first synthetic genome of a bacterium out of chemicals.

That work generated a lot of hype and considerable worry that scientists were tinkering with nature. Boeke said the work in his lab and many others is much less like "playing God" and more akin to genetic engineering, but on a broader scale.

Chromosome scrambling

For their designer yeast chromosome, Boeke and his team made more than 500 changes, removing repeating sections of nearly 50,000 base pairs of DNA they deemed unnecessary to chromosome reproduction and growth.

They also removed what has been called "junk DNA" - parts of the genetic code that do not make proteins - and segments known as "jumping genes," stretches of DNA that randomly hop around the genome and can cause mutations.

Despite all of those changes, Boeke said, "we still have a chromosome that works."

He is most excited about the ability to selectively delete or rearrange the letters of the chromosome, a process he calls chromosome scrambling. To make this happen, the scientists added in stretches of DNA known as loxP, a gene sequence that works as a genetic switch that can be activated by a protein.

"What's really exciting is in addition to yeast being healthy and happy, we've also endowed this chromosome with this almost magical property of being able to rearrange its structure when we wave our magic wand and generate millions of variant chromosomes," Boeke said.

Rare medicines and biofuels

Having the ability to produce new synthetic strains of yeast could result in some very useful types of yeast that could be used to make rare medicines, such as artemisinin for malaria, or certain vaccines, including for hepatitis B, which is derived from yeast, Boeke said.

And synthetic yeast could also be used to make more efficient biofuels, such as alcohol, butanol, and biodiesel.

Lei Wang, assistant professor in the Chemical Biology and Proteomics Laboratory at the Salk Institute for Biological Studies in La Jolla, California, said the work "will enable us to artificially speed up the evolution process in the lab."

Wang, who was not involved in the research, said he was impressed to see the yeast behaving normally after so many changes, which suggests "you can do very bold things to the organism."

Labs in United States, Britain, China and India are working toward making synthetic versions of all of the organism's 16 chromosomes by 2017, and Boeke thinks there could be at least one or two more yeast chromosomes published this year.